There is ample evidence to support the contention that new folate antagonists could be of great value in cancer chemotherapy. Prime targets are those neoplasias which possess natural or acquired resistance to amethopterin, 1b. Recently quinazoline analogs of 1b have been shown to be potent folate antagonists having significant anticancer activity. Since tetrahydrohomofolic acid, 4a, is an active compound which is effective against certain resistant cancers, the initial thrust of this program will be concerned with the synthesis and evaluation of quinazoline analogs of 4a. Systematic inhibition studies will be conducted with a large series of quinazolines against the three enzymes involved in the "thymidylate cycle", namely dihydrofolate reductase, thymidylate synthetase and serine transhydroxymethylase. Structure-activity relationships gained from these studies in conjunction with anticancer testing data will be employed in the design of new passive diffusion antagonists. Attention will be paid to the chemical properties of these compounds, in particular the solubility, in an effort to develop agents having the widest possible clinical utility.